The compound 5-hydroxytryptamine (5-HT or 5HT), also known as serotonin or enteramine, is a known vasoactive agent and endogenous neurotransmitter acting on receptors both within and outside the central nervous system and on blood vessels. Drugs acting on these receptors are known as 5-HT agonists or antagonists. These 5-HT receptors have been further classified into several receptor sub-classes, some of which themselves contain sub-types, and are designated, for example, 5-HT1, 5-HT1-like, 5-HT1.sub.B, 5-HT1.sub.D, 5-HT2, 5-HT3, and so on.
5-HT1-like agonists and agonists at other 5-HT1 sites comprise a known subclass of therapeutics with a variety of uses, notably including migraine therapy. Representative members of this class of compounds include sumatriptan succinate (distributed under the name Imitrex.TM. by GlaxoWellcome). Sumatriptan and related 5-HT agonist heterocyclic compounds are described in U.S. Pat. No. 4,816,470 to Dowle et al., the teachings of which are incorporated by reference. Note is made of ergot alkaloids which have 5-HT receptor activity, and these drugs are distinct from sumatriptan and its analogs in their chemical structure. In addition, ergots exhibit additional pharmacological properties distinct from sumatriptan. Ergot alkaloids and related compounds such as dihydroergotamine mesylate (DHE 45) are identified with 5-HT agonist receptor activities and have been used in migraine therapy. Without being bound by any particular theory, it is believed that the efficacy of ergots in relieving migraine arises, in part, from pharmacological activity distinct from the recognized 5-HT1 agonist property. Particular reference is made to ergotamine tartrate, ergonovine maleate, and ergoloid mesylates (i.e. dihydroergocornine, dihydroergocristine, dihydroergocryptine (dihydro-.alpha.-ergocryptine and dihydro-.beta.-ergocryptine), and dihydroergotamine mesylate.
Some of these agents are not reliably effective treatments for migraine. However, some agents are useful in the treatment of migraine, but after an initial therapeutic effect in some patients, migraine symptoms are seen again within about 1-24 hours after the initial relief. That is, after a dosage of a therapeutic agent has been administered to a subject in an amount to effectively treat a migraine, and migraine palliation has been observed, migraine symptoms occur again from as soon as about 1-8 hours after first relief to about 12 to 24 hours later. It will be appreciated that individual migraineurs display individualized symptoms and timing for this phenomenon as will treatment with particular therapeutic agents.
In some forms of migraine, certain patients have found total or partial relief with the use of analgesics such as acetaminophen and phenacetin and other non-steroidal non-opiate analgesics not generally classified as anti-inflammatory. While, these agents, when taken alone, are rarely effective in providing complete and rapid relief of all the symptoms of migraine, especially when the symptoms of the attack already include nausea or vomiting, in combination therapy of the present invention their effectiveness is surprisingly increased.
As outlined by K. M. A. Welch (New Eng. J Med, 1993:329; 1476-1483), the initial dosages of the analgesics useful for the treatment of migraine are: aspirin, 500-650 mg; acetaminophen, 500 mg; naproxen sodium, 750-825 mg; tolfenamic acid, 200-400 mg; and, ibuprofen 200 mg. After oral dosing, peak plasma concentrations in subjects not experiencing a migraine attack usually occur at or about 1 hour for aspirin and acetaminophen, and between 1-2 hours for naproxen sodium, tolfenamic acid, and ibuprofen.
The headache, which occurs under the circumstances described above, has been variously and interchangeably termed a "rebound," "relapse," "recurrent," or "secondary" headache. The terms not withstanding, it is presently unknown as to whether this later headache is a continuation of the physiological chain of events that caused original headache, or a new headache due to other or repeated but unrelated underlying pathology. It is also possible that the follow on headache is a response to therapeutic agents which initially were successful in treating the initial migraine symptoms. The terms "rebound", "relapse," "recurrent" and "secondary" (as defined below) are considered synonymous as used herein without inferring a mechanism or cause of the headache described above.
It has been reported that of the 50 to 70% of patients who experience migraine symptom relief within 2 hours from initial dosing with a 5-HT agonist, 30-50% experience migraine symptoms again within the next 1-24 hours. In view of the extreme discomfort and long duration of pain that characterizes migraine headaches, a therapy that reduces or avoids rebound migraine is of substantial importance.
Note is made of certain studies illuminating aspects of migraine therapy and of observed recurrent headache after treatment with a 5-HT agonist, the teachings of which are incorporated by reference.
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